Forming a chemically cross-linked particle of a desired shape and diameter

ABSTRACT

Chemically cross-linked polymeric particles are formed using mechanical rather than chemical processes, facilitating production of small-diameter particles in a manner largely independent of the viscosity or density of the polymer. For example, an uncross-linked resin may be provided in particulate form, agglomerated, and compressed into a mass of a desired shape with a desired diameter, and subsequently cross-linked.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of and claims priority toU.S. application Ser. No. 10/116,330, filed on Apr. 4, 2002 nowabandonded.

TECHNICAL FIELD

The invention relates generally to forming a chemically cross-linkedparticle and more particularly to forming a chemically cross-linkedparticle of a desired shape and diameter.

BACKGROUND INFORMATION

Polymeric microspheres (i.e., microspheres formed at least in part froma polymer) are used in medical and industrial areas. These microspheresmay be used as drug delivery agents, tissue bulking agents, tissueengineering agents, and embolization agents, for example. Accordingly,there are a variety of methods directed towards preparing polymericmicrospheres. Typical methods include dispersion polymerization of themonomer, potentiometric dispersion of dissolved polymer within anemulsifying solution followed by solvent evaporation, electrostaticallycontrolled extrusion, and injection of dissolved polymer into anemulsifying solution through a porous membrane followed by solventevaporation.

Additional methods of preparing polymeric microspheres include vibratoryexcitation of a laminar jet of monomeric material flowing in acontinuous liquid medium containing a suitable suspending agent,irradiation of slowly thawing frozen monomer drops, emulsification andevaporation, emulsification and evaporation using a high shear air flow,and continuous injection of dissolved polymer into a flowing non-solventthrough a needle oriented in parallel to the direction of flow of thenon-solvent.

SUMMARY OF THE INVENTION

The present invention facilitates production of microspheres havingsmall diameters in a manner that is generally independent of viscosityand density. This is accomplished through the use of an uncross-linkedpolymer precursor in solid form, and a mechanical technique ofcompacting the precursor into a desired shape.

Accordingly, in one aspect, the invention involves a method of forming achemically cross-linked particle of a desired shape and diameter. Themethod includes providing an uncross-linked resin (e.g., polyvinylalcohol) in particulate form, agglomerating the resin into a mass of adesired shape with a desired diameter, compressing the mass, andcross-linking the mass to thereby form the chemically cross-linkedparticle. An advantage of the present invention is the ability to avoidmelting the resin in order to attain the desired shape. This is useful,for example, in connection with thermally unstable polymers.

In one embodiment, the method further includes adding a binding agent(such as a starch or a sugar) to the resin and later removing thebinding agent by exposing the particle to a solvent formulated toselectively dissolve the binding agent. The binding agent serves to holdthe mass of uncross-linked resin particles together in the desired shapeuntil the mass is cross-linked. In other embodiments, the binding agentcomprises a polymer having a melting temperature lower than the meltingtemperature of the resin. In this way, the polymer becomes part of thechemically cross-linked particle.

In another embodiment, the method further includes cross-linking themass by exposing the mass to actinic energy such as an electron beam,ultraviolet radiation, or gamma radiation.

In still another embodiment, the method further includes cross-linkingthe mass by exposing the particle to a gaseous cross-linking agent.

In yet another embodiment, the method further includes agglomerating theresin into a mass in the shape of a sphere with a diameter of less than600 microns.

In another aspect, the invention involves a method of forming achemically cross-linked particle of a desired shape and diameter. Themethod includes providing an uncross-linked resin in particulate form,adding a binding agent to the resin, and agglomerating the resin into amass. The method further includes heating the mass to a temperature thatis both above the melting point of the binding agent and below themelting point of the resin, compressing the mass into a desired shapewith a desired diameter, and cooling the mass to a temperature below themelting point of the binding agent. The mass is then cross-linked toform the chemically cross-linked particle.

In one embodiment, cross-linking the mass includes exposing the mass toactinic energy, such as an electron beam, ultraviolet radiation, orgamma radiation.

In another embodiment, cross-linking the mass includes exposing the massto a gaseous cross-linking agent.

In still another embodiment, the method further includes removing thebinding agent by heating the chemically cross-linked particle to atemperature above the melting point of the binding agent. The bindingagent is thereby melted out of the chemically cross-linked particle.

In yet another embodiment, the method further includes removing thebinding agent by exposing the particle to a solvent formulated toselectively dissolve the binding agent.

The foregoing and other objects, aspects, features, and advantages ofthe invention will become more apparent from the following descriptionand from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, like reference characters generally refer to the sameparts throughout the different views. Also, the drawings are notnecessarily to scale, emphasis instead generally being placed uponillustrating the principles of the invention.

FIG. 1 is an illustrative flow diagram depicting the steps of forming achemically cross-linked particle of a desired shape and diameteraccording to one embodiment of the invention.

FIG. 2 is an illustrative flow diagram depicting the steps of forming achemically cross-linked particle of a desired shape and diameteraccording to another embodiment of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to FIG. 1, in one embodiment, the method of forming achemically cross-linked particle of a desired shape and diameter is amechanical process rather than a chemical process. First, anuncross-linked resin or polymer in particulate form is provided (Step102). In one embodiment, the resin is a polyvinyl alcohol resin inparticulate form having an average diameter of approximately 75 microns,such as a 99% hydrolyzed polyvinyl alcohol (e.g., product #341584 fromAldrich Chemical or Gohsenol NM-11 from Nippon Synthetic ChemicalIndustry Co.). In other embodiments, polymers such as polyvinyl acetate,vinyl polymers, polyamides, polyureas, polyurethranes, methacrylates,polyvinyl alcohols, or polymers having a pendant ester group that iseasily cross-linked (or derivatives thereof) can be used. For manyapplications (e.g., embolics), the polymer is desirably hydrophilic.

A binding agent is then mixed with the resin particles (Step 104). Thebinding agent serves to hold the resin particles together before theyare cross-linked. In some embodiments, the binding agent is a starch ora sugar (e.g., sucrose). In other embodiments, other materials such asalginates, polysaccharides, proteins, carrageenan, or vegetable gums,for example, can be used as binding agents. In still other embodiments,the binding agent can be a blend of one or more of the above syntheticor naturally occurring materials.

After the uncross-linked resin is mixed with the binding agent, theresin particles are agglomerated into a mass of a desired shape with adesired diameter (Step 106). In one embodiment, the resin particles areforced into a mold (using conventional plastic injection moldingtechniques) conforming to the desired shape and diameter. In anotherembodiment, the resin particles are pressed into the desired shape anddiameter using conventional compression equipment. In still anotherembodiment, a punch is used to punch the desired shape out of a solidsheet of the resin. In yet another embodiment, a combination of staticelectricity and mechanical vibration or agitation is applied to theuncross-linked resin to cause the uncross-linked resin to agglomerate.In another embodiment, the uncross-linked resin particles areagglomerated by being put into a suspension and rotated. Rotation forcesthe resin particles to collide with each other and form a mass that canthereafter be cross-linked. The size of the mass is selected bycontrolling the rate of rotation. As the rotation speed increases, sodoes the number of resin particle collisions. However, the forces actingto pull the agglomerated mass apart also increase. The final size of themass is a function of rotation speed and the force acting to pull themass apart.

Preferably, the technique used to form the particle involves, or isfollowed by, some form of compression in order to ensure that the resinparticles stay together in the desired shape, such as a sphere (Step108). For example, molding can involve pneumatic, hydraulic, or othercompression of the resin-filled mold form. Rotation generally providesadequate compression force.

After the mass is compressed, it is cross-linked to form the chemicallycross-linked particle (Step 110). In some embodiments, cross-linking themass is accomplished by exposing the mass to actinic energy, such as anelectron beam, ultraviolet radiation, or gamma radiation. In otherembodiments, cross-linking the mass is accomplished by exposing the massto a gaseous cross-linking agent such as formaldehyde, glutaraldehyde,or an acid, for example. Polyvinyl alcohol and other polymers can becross-linked using any of these techniques.

After the mass is chemically cross-linked and a chemically cross-linkedparticle is formed, the binding agent may be removed from the particleby exposing the particle to a solvent (Step 112) formulated toselectively dissolve the binding agent. For example, a polar solvent(e.g., water or alcohol) can be used to dissolve the binding agentsdiscussed above.

Referring to FIG. 2, in another embodiment, the binding agent is apolymer with a melting temperature that is lower than the meltingtemperature of the resin. First, an uncross-linked resin or polymer inparticulate form is provided (Step 202). Next, a binding agent is addedto the resin (204). After the uncross-linked resin is mixed with thebinding agent, the resin particles are agglomerated into a mass of adesired shape with a desired diameter (Step 206).

Exemplary binding agents useful in connection with this embodimentinclude Methocell methoylcellulose, hydroxypropyl methylcellulose,Ethocell Standard and Premium (organic solvent soluble) from DowChemical Co., Avicel PH-001 and Avicell PH-002 microcrystallinecellulose (water soluble) from Asahi Kasei Corp, potassium alginates,sodium alginates, or PEG 1400 (polyethylene glycol), for example. Theagglomerated mass of binding agent and resin is heated to a temperatureabove the binding-agent melting point but below the resin melting point(Step 208). After the mass is heated, it is compressed (Step 210).Compression ensures that the resin particles stay together in thedesired shape, such as a sphere, for example. After the mass iscompressed, it is cooled (Step 212). Upon cooling, the binding agentresolidifies and the shape imparted to the mass remains “set.”

After the mass is cooled, it is then cross-linked to form the chemicallycross-linked particle (Step 214). The binding agent may remain in theparticle during and following cross-linking of the resin. In someembodiments, cross-linking the mass is accomplished by exposing the massto actinic energy, such as an electron beam, ultraviolet radiation, orgamma radiation. In other embodiments, cross-linking the mass isaccomplished by exposing the mass to a gaseous cross-linking agent suchas formaldehyde or glutaraldehyde, for example. After the mass iscross-linked, the resulting particle can be again heated to atemperature above the binding-agent melting point so that the bindingagent can be melted out of the particle (Step 216). The binding agentmay also be removed from the particle by exposing the particle to asolvent formulated to selectively dissolve the binding agent. Forexample, a polar solvent (e.g. water or alcohol) can be used to dissolvesome of binding agents discussed above.

Variations, modifications, and other implementations of what isdescribed herein may occur to those of ordinary skill in the art withoutdeparting from the spirit and scope of the invention. Accordingly, theinvention is not to be defined only by the preceding illustrativedescription.

1. A method of forming a chemically cross-linked particle, the methodcomprising: providing an uncross-linked polyvinyl alcohol resin inparticulate form; agglomerating the resin into a mass; compressing themass into a sphere with a diameter of less than 600 microns; andcross-linking the mass to thereby form the chemically cross-linkedparticle.
 2. The method of claim 1 further comprising the step of addinga binding agent to the resin.
 3. The method of claim 2 wherein the stepof adding a binding agent comprises adding a starch.
 4. The method ofclaim 2 wherein the step of adding a binding agent comprises adding asugar.
 5. The method of claim 1 wherein the step of cross-linking themass comprises exposing the mass to actinic energy.
 6. The method ofclaim 5 wherein the step of exposing the mass to actinic energycomprises exposing the mass to one of an electron beam, ultravioletradiation, and gamma radiation.
 7. The method of claim 1 wherein thestep of cross-linking the mass comprises exposing the mass to a gaseouscross-linking agent.
 8. The method of claim 2 further comprising thestep of removing the binding agent by exposing the particle to a solventformulated to selectively dissolve the binding agent.
 9. A method offorming a chemically cross-linked particle, the method comprising:providing an uncross-linked resin in particulate form; adding a bindingagent to the resin, the binding agent having a melting point below amelting point of the resin; agglomerating the resin into a mass; heatingthe mass to a temperature above the melting point of the binding agentand below the melting point of the resin; compressing the mass into asphere with a diameter of less than 600 microns; cooling the mass to atemperature below the melting point of the binding agent; andcross-linking the mass to thereby form the chemically cross-linkedparticle.
 10. The method of claim 9 wherein the binding agent is apolymer, the polymer becoming part of the chemically cross-linkedparticle.
 11. The method of claim 9 wherein the step of cross-linkingthe mass comprises exposing the mass to actinic energy.
 12. The methodof claim 11 wherein the step of exposing the mass to actinic energycomprises exposing the mass to one of an electron beam, ultravioletradiation, and gamma radiation.
 13. The method of claim 9 wherein thestep of cross-linking the mass comprises exposing the mass to a gaseouscross-linking agent.
 14. The method of claim 9 further comprising thestep of removing the binding agent by heating the chemicallycross-linked particle to a temperature above the melting point of thebinding agent thereby melting the binding agent out of the chemicallycross-linked particle.
 15. The method of claim 9 further comprising thestep of removing the binding agent by exposing the particle to a solventformulated to selectively dissolve the binding agent.
 16. A method offorming a chemically cross-linked spherical particle, the methodcomprising: providing in particulate form an uncross-linked resinselected from the group consisting polyvinyl alcohol, polyvinyl acetate,vinyl polymers, polyamides, polyureas, and methacrylates; agglomeratingthe resin into a mass; compressing the mass into a sphere with adiameter of less than 600 microns; and cross-linking the mass byexposing the mass to radiation, to thereby form the chemicallycross-linked spherical particle.
 17. The method of claim 16, furthercomprising the step of adding a binding agent to the resin, wherein thebinding agent comprises sucrose.
 18. The method of claim 17, furthercomprising the step of removing the binding agent by exposing theparticle to a solvent formulated to selectively dissolve the bindingagent.
 19. The method of claim 16, further comprising the step of addinga binding agent to the resin, wherein the binding agent comprises astarch.
 20. The method of claim 19, further comprising the step ofremoving the binding agent by exposing the particle to a solventformulated to selectively dissolve the binding agent.
 21. The method ofclaim 16, wherein the step of cross-linking the mass comprises exposingthe mass to radiation selected from the group consisting of electronbeam radiation, ultraviolet radiation, and gamma radiation.
 22. Themethod of claim 16, wherein the step of cross-linking the mass comprisesexposing the mass to formaldehyde or gluturaldehyde.
 23. A method offorming a chemically cross-linked particle, the method comprising:providing an uncross-linked resin in particulate form; agglomerating theresin into a mass; compressing the mass into a sphere with a diameter ofless than 600 microns; and exposing the mass to actinic energy tocross-link the mass to thereby form the chemically cross-linkedparticle.
 24. The method of claim 23 further comprising the step ofadding a binding agent to the resin.
 25. The method of claim 24 whereinthe step of adding a binding agent comprises adding a starch.
 26. Themethod of claim 24 wherein the step of adding a binding agent comprisesadding a sugar.
 27. The method of claim 24 further comprising the stepof removing the binding agent by exposing the particle to a solventformulated to selectively dissolve the binding agent.
 28. The method ofclaim 23 wherein the step of exposing the mass to actinic energycomprises exposing the mass to one of an electron beam, ultravioletradiation, and gamma radiation.
 29. The method of claim 23 wherein theresin comprises a polyvinyl alcohol resin.
 30. A method of forming achemically cross-linked particle, the method comprising: providing anuncross-linked resin in particulate form; agglomerating the resin into amass; compressing the mass into a sphere with a diameter of less than600 microns; and exposing the mass to a gaseous cross-linking agent tocross-link the mass to thereby form the chemically cross-linkedparticle.
 31. The method of claim 30 further comprising the step ofadding a binding agent to the resin.
 32. The method of claim 31 whereinthe step of adding a binding agent comprises adding a starch.
 33. Themethod of claim 31 wherein the step of adding a binding agent comprisesadding a sugar.
 34. The method of claim 31 further comprising the stepof removing the binding agent by exposing the particle to a solventformulated to selectively dissolve the binding agent.
 35. The method ofclaim 30 wherein the resin comprises a polyvinyl alcohol resin.
 36. Amethod of forming a chemically cross-linked particle, the methodcomprising: providing an uncross-linked resin in particulate form;agglomerating the resin into a mass; compressing the mass into a spherewith a diameter of less than 600 microns; and cross-linking the mass tothereby form the chemically cross-linked particle.
 37. The method ofclaim 36 further comprising the step of adding a binding agent to theresin.
 38. The method of claim 37 wherein the step of adding a bindingagent comprises adding a starch.
 39. The method of claim 37 wherein thestep of adding a binding agent comprises adding a sugar.
 40. The methodof claim 37 further comprising the step of removing the binding agent byexposing the particle to a solvent formulated to selectively dissolvethe binding agent.
 41. The method of claim 36 wherein the step ofcross-linking the mass comprises exposing the mass to actinic energy.42. The method of claim 41 wherein the step of exposing the mass toactinic energy comprises exposing the mass to one of an electron beam,ultraviolet radiation, and gamma radiation.
 43. The method of claim 36wherein the step of cross-linking the mass comprises exposing the massto a gaseous cross-linking agent.